RELEVANCE: Annually, more than 700,000 primary hip and knee replacements and another 1.2 million spine surgeries are performed on VA and non-VA patients in the United States (US). Perioperative device-related infections compromise approximately 2-3% of these primary procedures and when considering revision surgeries, this number grows as high as 17.5%. Infections following these procedures are difficult to treat, especially in cases where antibiotic-resistant bacteria have been identified as the pathogenic species. These resistant bacteria may be present in the form of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus (VRSA), or similar resistant bacterial strains. Estimates of veteran and nonveteran hospital acquired S. aureus and MRSA infections are reported at nearly 500,000 cases in the US each year. This increase in the number of MRSA cases has been attributed to the bacteria's evolving resistance toward conventional antibiotic therapy. OBJECTIVES: The objective of this study is to combat resistant bacterial strain infections associated with common orthopedic device procedures using a unique silicone (Si) polymer released cationic steroidal antimicrobial-13 (CSA-13) in a sheep animal model. The long-term goals of this work are to reduce the incidence of device-related infection, minimize the time required for hospitalization, decrease the expense incurred by the VA Health Care System and patient, and eliminate multiple-stage revision procedures. HYPOTHESES: 1) The 18% weight-to-weight ratio (w/w) CSA-13 in Si polymer combination coating will prevent infection caused by planktonic MRSA in vivo when eluted from the Si polymer coating on a porous coated titanium plug implant. 2) The rate and amount of periprosthetic skeletal attachment within the porous coated region of the plug implant will not be adversely affected by the release of the CSA-13 antimicrobial. PROCEDURES: To test Hypothesis 1 two study groups will be challenged with 200 L of 5x108 colony forming units of planktonic MRSA in phosphate buffered saline. A porous coated titanium (Ti) plug will be implanted into the articulating surface of the right femoral condyle and run for 4 weeks. The infection control (Group 1) will receive a porous coated Ti plug and MRSA suspension to ensure that an infection signal has been generated. The infection challenge (Group 2) will receive a Ti plug coated with a thin film of Si containing the CSA-13 antimicrobial (18% w/w) and MRSA suspension to test the bactericidal efficacy of CSA-13. To test Hypothesis 2 three groups will be utilized to assess the biocompatibility of the CSA-13 combination coating- no MRSA will be used to test Hypothesis 2. The biocompatibility challenge (Group 3) will receive the 18% (w/w) CSA-13/Si coated plug to characterize the effects of CSA-13 on the periprosthetic bone. The polymer control (Group 4) will receive a Si coated plug (without CSA-13) to assess the effects of the polymer, alone, on the adjacent bone to distinguish the effects of CSA-13 from the Si on skeletal attachment. Finally, the biocompatibility control (Group 5) will receive only the porous coated Ti plug-without CSA-13 or Si to demonstrate skeletal attachment in a material with established biocompatibility. Similar to Hypothesis 1 the plug will be implanted in the right femoral condyle and two time points will be utilized to assess biocompatibility: 4 and 24 weeks. SIGNIFICANCE OF FINDINGS: The success of this antimicrobial combination coating has the potential to significantly improve VA clinical care by reducing costs associated with primary and revision surgeries caused by perioperative device related infections. This research would also greatly improve the veteran's quality of life and reduce the time required for hospitalization and rehabilitation by eliminating, or significantly limiting, the veteran's susceptibility to perioperative device related infections.